Breast cancer kills thousands of women annually. While surgical intervention has saved the lives of many women, radical and partial mastectomies often prove physically and emotionally debilitating. Moreover, patients who have undergone surgery and subsequent chemotherapy often experience recurrence.
Drugs for preventing or treating breast cancer, as well as other cancers, are desirable, and many research efforts have focused on the development of such drugs. One such drug is retinoic acid, a metabolite of vitamin A. Retinoic acid and certain amide analogs of this compound display cancer preventive activity and, thus, have been proposed as cancer chemopreventive agents (Moon et al. Cancer Res. (1979) 39, 1339-1346). Similarly, other retinoic acid analogs such as retinyl acetate, 13-cis-retinoic acid, and glucuronide analogs of retinoic acid also display cancer preventive activity, including breast cancer preventative activity (Hill, D. L. et al. Ann. Rev. Nutrition (1992) 12, 161-181 and Mehta, R. G. et al. Oncology (1991) 48, 1505-1509).
Unfortunately, retinoic acid and most of its closely related analogs exhibit relatively high toxicity, thus impeding their use in humans (Biesalski, H. K. Toxicology (1989) 57, 117-161). Use of most of these compounds results in side effects such as teratogenicity, hepatotoxicity, scaly skin, hair loss and headaches. Accordingly, researchers have continued to pursue the synthesis of retinoic acid analogs with increased potency and/or reduced toxicity for application as cancer preventative agents.
It has also been found that N-(4-hydroxyphenyl) retinamide (hereinafter “4-HPR”), an analog of retinoic acid, displays chemopreventive activity in breast cancer (Moon et al. Cancer Res. (1979) 39, 1339-1346). Indeed, 4-HPR, when combined with calcium glucarate, synergistically exerts an increased breast cancer chemopreventive activity in carcinogen-induced rat mammary tumors (Abou-Issa, H. M. et al. (1988) Proc. Natl. Acad. Sci. USA 85, 4181-4184). However, 4-HPR still displays teratogenic potential as evidenced by studies in the rat, mouse and the rabbit. (See Kenel, M. F., Krayer, J. H., Merz, E. A. and Pritchard, J. R. (1988) “Teratogenicity of N-(4-hydroxyphenyl)-all-trans retinamide in rats and rabbits.” Teratogenesis, Carcinogenesis and Mutagenesis 8:1-11; Kochhar, D. M. Shealy, Y. F., Penner, J. D. and Jiang, H. (1992) “Retinamides: hydrolytic conversion of retinoylglycine to retinoic acid in pregnant mice contributes to teratogenicity.” Teratology 45:175-185.) Furthermore, 4-HPR impairs night vision in human patients (Kaiser-Kupfer, M. I., Peck, G. K., Caruso, R. C., Jaffe, J D., DiGiovanna, J. J., Gross, E. G. (1986) “Abnormal retinal function associated with fenretinide, a synthetic retinoid.” Arch Ophthalmol.104:69-70.; Costa, A., Malone, W., Perloff, M., Buranelli, F., Campa, T., Dossena, G., Magni, A., Pizzichetta, M., Andreoli, C., DelVecchio, M., Formelli, F., and Barbier, A. (1989) “Tolerability of the synthetic retinoid Fenretinide (HPR).” Eur. J. Cancer Clin. Oncol. 25:805-808).
Thus, there still remains a long-felt need to have stable chemopreventive drugs for the prevention and treatment of various cancers, including breast cancer.